David2 - University of Ljubljanalbk.fe.uni-lj.si/pdfs/bemd2004.pdf · The inﬂammatory phase refers to immediate vascular and inﬂammatory response to injury. The immediate response

31Electric Current Wound Healing

David Cukjati

Laboratory of Biocybernetics, Faculty of Electrical Engineering,Ljubljana, Slovenia

Rajmond Savrin

Institute for Rehabilitation, Republic of SloveniaLjubljana, Slovenia

The authors review the existing physical modalities for treatment of chronicwounds and show the advantages of electric current and electromagnetic fieldstimulation. Direct currents, low frequency pulsed currents, monophasic highvoltage pulses and pulsed electromagnetic fields are compared in respect of theirefficiency. Wound healing quantification methods, wound healing dynamics andprognostic factors in the prediction of wound healing proposed by the authorsrepresent significant contribution in understanding the mechanisms of electricwound healing.

I. WOUND HEALING

Skin is a vital organ, in the sense that the loss of substantial fraction of its mass immediatelythreatens the life of the individual. A cutaneous wound is any loss of skin integrity. Such aloss can result suddenly, either from fire or mechanical accident, or it can occur in a chronicmanner due to illness, as in skin ulcers. Since intact skin is of vital importance to protect theorganism against environment, regenerative mechanisms must be activated to resolve adefect. Cutaneous wound healing is a dynamic biological process that begins with tissueinjury. It has several goals:

The discontinuation of further injuryThe recruitment of injured cellsThe formation of new tissueThe remodeling of the new tissue to best approximate the preinjury form and function.

These events have traditionally been divided into three overlapping phases: an infla-

485

The inflammatory phase refers to immediate vascular and inflammatory response toinjury. The immediate response to blood vessel disruption is activation of the coagulationcascade and the production of blood clot. After several minutes, an acute inflammatoryresponse ensues. Subsequently, leukocytes clear the wound of debris and release growthfactors to initiate the healing process. Then follows the proliferative phase involvingdeposition and formation of granulation tissue, which becomes a new and temporary weaktissue, reepitelization, and wound shrinkage. The maturation phase is characterizedclinically by gradual shrinking, thinning, and paling of the scar, leading to decreased bulkbut increased tensile strength (1). If any of three overlapping phases of cutaneous woundhealing is suppressed, wound healing is prolonged or even prevented. Reasons for slower orretarded healing can be local, such as bacterial infection that prolongs the inflammatoryphase; lower oxygen tension that prolongs the proliferative phase; or systemic, such asinjuries of the nervous system, diabetes mellitus, atherosclerosis and other vascular diseases,metabolic and ageing problems that affect one or more phases of wound healing.

When conservative methods of wound care cannot facilitate wound healing, the woundis considered to be chronic. Such chronic wounds can last for weeks, months, or even yearsdespite adequate and appropriate care. They are difficult and frustrating tomanage. Typicalchronic wounds are pressure ulcers in spinal-cord-injured patients, ischemic ulcers in lowerextremities of patients with peripheral vascular disease, ulcers in geriatric patients, andwounds after limb amputations (2). Patients are subjected to discomfort, stress, and highcost of long-term conventional treatment required for such ulceration to heal.

According to statistic reports, 11% of all hospitalized patients and up to 20% of allelderly home residents suffer from decubital wounds (3). The frequency of decubital woundsin spinal-cord-injured (SCI) patients is quite diverse, ranging from 23% to as much as 85%/year (4). The percentage of SCI patients that will end up with at least one decubital wound intheir lifetime is 85% (5–7). Decubital wounds may be directly responsible for death of 7–8%of patients, while frequently an indirect influence upon the mortality rate through differenthealth complications, such as osteomyelitis or sepsis (8). Diabetic foot ulcers are a commonproblem and result inmore than 85,000 lower extremity amputations each year in theUnitedStates. Studies were employed to find the most cost effective treatment of nonhealingwounds (9).

Chronic wound healing represent a major social, medical and economic problem.Therefore an extensive effort has been done to find any treatment modality, which mayaccelerate the wound-healing process.

II. TREATMENT OF CHRONIC WOUNDS

The understanding of the biological and pathologic events in wound healing has led to threeareas of treatment that are currently indicated for the treatment of chronic wounds in theclinic practice (10): grow factors, tissue engineered skin, and physical devices. Despite thevast interest in growth factors and cytokine biology and their potential for wound healing(11,12), clinical trials to accelerate chronic wound healing have in most cases beendisappointing. Nevertheless several studies have shown that the application of growthfactors may induce the acceleration of cutaneous wound healing in animal models (13).Tissue engineered skin offers the possibility of creating physiologically compatible humanskin and are successfully used on burn wounds to prevent bacterial infection and allow thewound the chance to heal by normal reparative processes. Unlike in burn patients, thecondition in patients with chronic wounds results from underlying diseases therefore closingwound with skin substitutes would not be sufficient to initiate the wound healing (14). A

CUKJATI AND SAVRIN486

review of the literature revealed that many adjunctive physical devices were employed andreported to facilitate chronic wound healing, including wound dressings (15), low-level lasertherapy (16), low-intensity laser therapy–combined phototherapy (17), ultrasound (18),ultrasound/ultraviolet treatment (19), hyperbaric oxygen (20), electric current stimulation(21,22) and magnetic–electromagnetic field stimulation (23).

According to Sheffet et al. (24) only two treatment-related recommendations receivehigh ratings for reported experimental evidence of validity: use of moist wound dressingsand adjunctive electrical stimulation for nonhealing wounds. The recent reviews of literaturerevealed advances in the knowledge of electrical wound healing.

III. ELECTRIC CURRENT AND ELECTROMAGNETIC FIELDSTIMULATION

Electrical interactions are regulators of many basic physiological processes ranging fromconformation of molecules within a cell membrane bilayer to the macroscopic mechanicalproperties of the tissues. However, there is no well-established mechanism that can explainhow weak electric currents and electromagnetic field (EMF) applications affect the behaviorof living cells and tissues. The use of electric current andEMF stimulation to enhancewoundhealing is not new. The pioneer clinical studies range in late 1960s (25). In recent years,electric current and EMF stimulation (electrical stimulation) have become increasinglypopular treatment modalities of nonhealing wounds. Electrical stimulation was primarilyused to accelerate healing of decubitus ulcers and vein insufficiency. Studies revealed thatpressure sores react better on electrical stimulation than other types of wounds (26). In theliterature following positive effects of electrical stimulation on chronic wound healing can befound:

Accelerated epitelization and healing

Higher percentage of healed wounds in comparing to conservative treatment andactivation of healing when conventional treatment failed

Prevention of tissue necrosis and antibacterial effect

Improved blood circulation

Increased wound contraction

Higher scar elasticity

Increased response of fibroblasts

Decrease of neuropath pain

Decreased peripheral neuropathy

There have been many excellent reviews published on electrical wound healing(21,22,24,27). The results of the first meta-analysis showed that electrical wound healingis effective adjective therapy for chronic wound healing, while relative effectiveness ofdifferent types of electrical wound healing is inconclusive (28). Nevertheless, more recentmeta-analysis on selected pooled trials could not constitute acceptable proof that electricalstimulation has specific effect on health (29). The survey of existing literature indicates avariety of electric and electromagnetic modalities that have been developed to heal wounds(Table 1) (30–35). Only little uniformity can be found in the literature reporting the use ofelectrical stimulation with respect to electrical signal properties, placement of stimulationelectrodes, and treatment regime. Although electrical stimulation produces a substantialimprovement in the healing of chronic wounds, further research is needed to identify which

ELECTRIC CURRENT WOUND HEALING 487

Table

1Diversity

ofElectricalStimulationModalities

forChronic

WoundHealing

Stimulationtype

Applicationtime

Electrodepolarity

andplacement

Wounds

Directcurrent,

0.2–1mA

(25)

2hofstim

ulation,4h

pause,threetimes

aday.

Negativeelectrodeover

ulcer,change

ofpolarity

aswoundprogressed.

Ischem

iculcers

Highvoltagepulses,100–175V,

frequency

of105Hz(30)

45min/day,5daysaweek

Positiveelectrodeover

ulcer,sw

itched

ifwoundhealingplateauisreached.

Decubitusulcers

Monophasicpulsed

current

(frequency

of128pps,64pps

aswoundprogressed,peak

amplitudeof29.2

mA)(31)

30min,tw

icedaily.

Negativeelectrodeover

ulcer,polarity

waschanged

every3daysanddaily

aswoundprogressed.

Pressure,vascularulcers,

traumaorsurgerywounds

Alternatingconstantcurrent

square

wavepulses

(80pps,

pulsewidth

1ms,intensity-

evokingparesthesias)

(32)

20min

twicedailyfor

12weeks

Electrodes

placedoutsidetheulcer

surface

area,polarity

waschanged

after

each

treatm

ent.

Diabetic

ulcers

Asymetricbiphasicpulses

(40pps,amplitudeupto

35mA)in

trainslasting4s,

followed

by4spause.(33)

30,60,or120min/day

Electrodes

placedontheintact

skin

symmetricallyonopposite

sides

ofthewound.

Pressure

ulcers

Directcurrent,0.6

mA

(34)

2h/day

Positiveelectrodeoverlaid

theulcer.

Pressure

ulcers

Asymmetricandsymmetric

biphasicsquare

wavepulses,

frequency

of50pps,

amplitudebelow

contraction(35)

90min/day

Electrodes

placedontheintact

skin

symmetricallyonopposite

sides

ofthewound.

Ischem

iculcers


electrical properties are most effective and which wounds response to this best. In followingsubsections electrical waveforms used in electrical wound healing are divided into sub-sections: direct current, low-frequency pulsed currents, monophasic high-voltage pulses,and pulsed electromagnetic fields.

A. Direct Current Electrical Stimulation

In normal, uninjured human skin, a difference in ionic concentrations is actively maintainedbetween the upper and lower epidermal layer, which can be measured as a difference ofelectrical potentials, ranging between 10 and 60 mV on different locations on the bodysurface. The positive terminal of this so-called epidermal battery is located on the insidesurface of the living layer of the epidermis (36). After wounding, when the skin layers areinterrupted, the epidermal battery at the wound site is short-circuited, producing aconducting pathway, which allows ionic current to flow through the subepidermal regionout of the wound and return to the battery by flowing through the region between the dermisand the living layer. The injury current (in AA range) can only flow, as along as woundsurface is moist. The active role of endogenous electrical phenomena in wound healing isindirectly confirmed by the fact that the healing of wounds, the surface of which is keptmoist, is more successful than in wounds that are left to dry out. Modeling of wound edgehas shown relatively steep lateral voltage gradient across the edge, whichmeans that the cellson the wound edge are situated in an electric field (34). Electric fields on order 100–200 mV/mm have been measured lateral to wounds in mammalian epidermis.

Endogenous wound-induced electric fields present in the cornea plays role in the healingprocess by helping guide the cellular movements that close wounds. It has been shown thatexternally applied electrical fields of such ‘‘physiological’’ intensities can affect orientation,migration, and proliferation of cells (37), which are of key importance for healing, such asfibroblasts and keratinocytes (38–41). Several studies have confirmed that externallyinduced electrical fields with endogenous electrical conditions, positive electrode on thewound surface, and negative on the healthy skin around the wound, accelerate woundhealing. Electrical currents were in range from 0.2 mA to 1 mA. The application of negativeelectrode on wound surface was reported to have antimicrobial effect (25,42) and wasstipulated to be useful in initial stage of treatment.

B. Low Frequency Pulsed Electric Currents

Low-frequency pulsed electric current applications are quite popular in physical medicine.They are most commonly used for functional electrical stimulation to provoke involuntarymuscle contraction for strengthening muscles atrophied by disuse and for eliciting func-tional movements in patients with motor disfunction (43,44). Such electric current pulses arealso known as tetanizing currents. Low-frequency pulsed electric currents were not appliedonly locally to the wound but also to areas quite distant to the wound. The twomajor distantlocations were the spinal cord and acupuncture points (21). When low-frequency pulsedelectric currents are applied locally both electrodes are placed on the healthy skinsurrounding the wound. The amplitude of pulses is set to value just below visible tetaniccontraction of surrounding muscles. This treatment modality is noninvasive and simple touse. The formation of chronic wounds is principally caused by an insufficient supply ofoxygen and nutrients to the tissues due to poor blood flow. Daily use of low-frequencypulsed electric current stimulation was found to significantly increase partial oxygen tension(pO2) around the chronic wound while no significant changes of pO2 were found when direct


current electrical stimulation was used (45). Increase of pO2 during low-frequency pulsedelectric current stimulation in patients with ischemic ulcers was caused by beneficial effectson the microcirculation. It is assumed that hypoxia or the release of metabolites duringelectrical stimulation due to insufficient blood flow and lack of oxygen represents stimuli forcapillary growth.

C. Monophasic High-Voltage Pulses

Muscle is contracted at application of low pulse amplitudes and longer durations as well asat large amplitudes and shorter pulse durations. For the use of short high-voltage pulses nophysiological explanation could be found. The positive electrode is placed over the woundand voltage set just below that capable of producing visible muscle tetanic contraction. Thepolarity of electrode over the wound was reversed if treatment reached the healing plateau.Reversing electrode polarity was successful when wounds were infected. Negative electrodeplaced on the wound has disinfection effect. It is reported that high-voltage stimulationimproves blood flow and therefore facilitate wound healing (30,46). It is hypothesized thathigh-voltage pulses stimulation restores sympathetic tone and vascular resistance below thelevel of the spinal cord lesion, thereby increasing the perfusion pressure gradient in thecapillary beds. As such, high-voltage pulses stimulation could be used for preventingpressure ulcers (47).

D. Pulsed Electromagnetic Fields

Since experimental and clinical data suggested that exogenous electromagnetic fields (EMF)at low levels can have a profound effect on a large variety of biological systems, this led to theuse of EMF signals in the treatment of large variety of diseases. It is successfully usedclinically in all areas of bone fracture management (48,49). The effect of noninvasive EMFon soft tissues is less well defined and it remains unclear though in vivo animal experiments,in vitro cell research and selected clinical studies confirmed accelerated wound healing.Markov and Pilla (27) in their detailed review of EMF stimulation of soft tissues discussmechanisms of EMF treatment of nonhealing wounds.

IV. WOUND-HEALING QUANTIFICATION METHODS

Despite the fact that different research groups have demonstrated that electrical stimulationcan accelerate wound healing, it is still not widely used. Universal efficiency of electricalstimulation, diversity of small studies, unsuitable wound healing quantification methods,and not well established mechanisms that can explain how electrical stimulation affect thebehavior of living cells and tissues render optimization of electrical stimulation difficult. Dueto different quantification methods used, it is impossible to make a quantitative analysis ofthe comparative advantages and disadvantages of different treatmentmodalities. In order toenable quantification and comparison of treatment efficacy, uniform measure of woundhealing needs to be generally accepted, which ideally would fulfill the following criteria:simple calculation, suitable for statistical handling, transparency—evident physiologicalmeaning, employability for different wound types, sizes, shapes, and healing and/or non-healing courses. Quantitative measurement of wound healing should enable service pro-viders to assess, improve, and individualize the treatment given to each wound patient. Inorder to correctly quantify wound healing wound has to be periodically assessed and woundhealing process dynamics has to be considered.


A. Wound Status Assessment

Wound assessments provide the foundation of the plan of care and are the only means ofdetermining the effectiveness of the treatment. Regular reassessments are crucial in clinicaltrials and practice to provide the care provider an insight into the time course of the woundhealing by comparing the series of wound data collected over time (50). Documentedreassessments can be reanalyzed for treatment optimization. Chronic wound assessmentrequires quantification of multiple parameters of the wound and surrounding tissue.Lazarus et al. (51) proposed guidelines for wound assessment. They listed attributes thatare clues to the cause, pathophysiology, and status of the wound. Clinical assessment shouldinclude wound history, anatomic location, stage, size, sinus tracts, undermining, tunneling,exudate or drainage, necrotic tissue, presence or absence of granulation tissue, andepithelization. Intact skin surrounding the wound should be assessed for redness, warmth,induration or hardness, swelling, and any obvious signs of clinical infection (52).

Assessment of wound status should begin with the extent of the wound. Because theextent of the wound changes with time, it requires periodic assessments. There are severaltechniques that may be employed to assess wound extent. To be clinically acceptable, theassessment of chronic wound healing has to be noninvasive, inexpensive, and practicalenough to be regularly used by clinicians. In several past years number of studies to enhancetools for monitoring healing steeply increased. Studies were primarily focused on periodicalnoncontact wound status assessments and their documenting. Noncontact systems forwound status assessment base onwound sizemeasurements, mostly onwound area. Systemsare in various phases of testing on plaster molds and animal wound models:

Structured lighting pattern captured on a digital photograph of a wound can be usedto calculate the area and volume of debrided wound (53,54).

Computer assist planimetric methods using digitalized tracings of the wound (55).

Three-dimensional laser imaging system for wound area and volume assessment (56).

Digital imaging technique and planimetry for wound area assessment (57).

Laser scanner for wound topography measurement and calculation of wound volumeand area assessment (58).

The literature reveals that assessment of wound area, wound perimeter, or mutuallyperpendicular diameters (largest diameter of the wound and diameter taken at right angleto the largest one) are most frequently used. Classical wound volume and depth assessmenttechniques are invasive because we have to insert our measuring device or material (dentalmoulds) into the wound (59). Besides the disturbance of the wound, the volume or depth canbe underestimated because of invisible edge at the bottom of the wound and degenerativetissue, which fills up thewound. Invasivemeasurementmethods could interfere with healing;therefore, they are generally avoided. Noncontact methods require expensive equipmentsuch as stereoscopy, MRI (60) or above described novel techniques and are rarely used.Since wounds are often irregular in shape and heal asymmetrically, different estimates ofwound area are used. Acetate tracings can provide the most accurate description of woundarea and perimeter but require manual or computer planimetry. Automatic wound contourdetection methods from digitized images of wounds could in future simplify wound areaassessment (61). Estimates of wound area can be calculated from the product of twomutually perpendicular perimeters or by calculation of the area of a circle or ellipse frommeasured diameters. Surface area can also be estimated by simply comparing ulcers topredrawn circles or ellipses of known area. Results of studies suggest that simple and cost-


effective wound area measurement techniques such as ellipse estimate may confidently beused to monitor healing in clinical settings (62–64).

Another wound status assessment possibility is scaling systems where scaling of woundstatus is determined by one or several indicators of wound healing such as wound extent,necrosis, surrounding skin color, peripheral tissue edema and induration, granulation tissue,epithelialization, infection, drainage, eschar and exudates. Shea, in 1975 was one of the firstto propose a standardwound classification system (65). It was basedmainly onwound depthand did not focus on presence or absence of infection. Additionally, the system did notmention ischemia as a co-morbid factor. Because of these limitations, several classificationsystems have been proposed since then (66). There are three widely accepted criteria used toclassify the stages of ulcers. The most widely used pressure ulcer scaling system is the fourstage system developed by the National Pressure Ulcer Advisory Panel (NPUAP), MerckManual for decubitus ulcers, and Wagner’s Classification system for foot ulcers. NPUAPwarns that staging should not be used to determine progress toward the wound healing,because stage IV pressure sore is always a stage IV ulcer no matter how it is healing. For thisreason several classification systems have been proposed, that are responsive to changesduring wound healing. These systems are still in various stages of testing, but two of themostpromising appear to be the seven point categorical Sessing scale (67) and Pressure UlcerScale for Healing (PUSH) (68). Recently PUSH systemwas demonstrated on clinical data tobe valid and sensitive measure of pressure ulcer healing (69) with the components of lengthtimes width, exudates amount, and tissue type, though further testing is needed to confirmthese findings. Scaling systems are widely used as awound assessment alternative, as they arepractical for daily monitoring. However it is still not clear if it is appropriate to use them forthe follow-up of changes in wound healing. The small number of stages makes them easy touse but at the same time makes them not sensitive enough for wound healing progressdescription (70). Based on above considerations wound extent should be evaluated formonitoring wound status when progress toward the wound healing has to be determined.

B. Wound-Healing Process Dynamics

If assessment of wound extent is a quantitative value (a scalar) and is periodically assessed,linear or nonlinear regression can reveal wound healing dynamics over time. Themajority ofresearchers use measures of wound extent that incorporate only wound area, while woundvolume, depth, and perimeter are rarely used. Gilman (71) defined a measure of woundextent that incorporated wound area and perimeter and was termed the advance of thewound margin toward the wound center. Wound extent is mostly defined either as absoluteor normalized wound area. Normalized wound area is calculated as wound area divided bythe initial wound area and multiplied by 100. Dynamics of the healing processes followedeither by measuring absolute or normalized wound area over time are the same.

Researchers generally use either linear or exponential models to present time course ofwound-healing process. Both models are distinguished for small number of parameters,however, neither of models has an adequate physiological basis. Most prominent disad-vantage of the linear model is that it sets no limit to wound area. Recent research revealedthat time course of wound area had in 51% of wounds included in the study decayexponential shape after initial delay longer than 3.5 days. In 40% of wounds the delaywas more than 7 days and in 26% of wounds the delay was more then 14 days. Exponentialmodel correctly described only 49% of time courses of wound area during healing. Toconsider the observed initial delay of healing a delayed exponential model was proposed forthe most general mathematical model of chronic wound-healing dynamics (72). An example


of such wound-healing dynamics is presented in Fig. 1 and amathematical description of thedelayed exponential model is given by Eq. (1),

S tð Þ ¼SDEX 0 V t < TDEX

SDEXe�hDEX t�TDEXð Þ t z TDEX

8<: ð1Þ

where S tð Þ is the estimated wound area in percent of initial wound area and three parametersSDEX, uDEX and TDEX describe the wound healing dynamics. Parameter SDEX (%) estimatesinitial wound area, and parameter uDEX (day�1) defines the time constant of exponentfunction and time delay of the healing process is defined by parameter TDEX (day). It hasbeen demonstrated that this model has good predictive capability and in this capacity can beused to predict time needed to complete wound closure after at least 4 weeks of consecutiveweekly measurements of wound area. Such model may be very useful in clinical trials, wherenot all wounds included in the study close within the designated study period.

Incorporating wound shape information (through wound perimeter) in wound extentmeasure did not improve wound healing dynamics description (73). Since it is easier tomeasurewound area thanwound area and perimeter, estimation of wound healing dynamicsfrom regular wound area measurements is preferred.

C. Wound-Healing Rate Definition

In spite of the evident need for uniform measure of wound healing rate, several measureshave been employed in literature to date. The first group of wound healing rate measuresbase either on wound size assessments the beginning of the observation period and at its endor on periodical wound size assessments in the observation period. Wound healing rate wasestimated as percentage reduction of wound area in 4 weeks (74), as percentage reduction ofwound area in 12 weeks (32), as percentage reduction of wound area per day in observation

Figure 1 Example of following wound area and application of the delayed exponential model tonormalized data. SDEX, uDEX, TDEX are calculated parameters of the delayed exponential model, andQrelative is a measure of wound healing rate. (–) Fitted delayed exponential model; (.) normalizedwound area (from Ref. 73).


period (75), as average percentage reduction of wound area per week in 4 weeks (31), asaverage of the sequentially computed weekly healing rates (normalized difference betweentwo sequential measurements) in percent of initial wound area per week (35), as time neededto complete wound closure (76), as average linear healing of the wound edge toward thecenter after 2 weeks in distance per day (77), and as time constant of exponential function fittoweeklywound areameasurements (33). The second group ofwound healing ratemeasuresbase on changes in scorings, assessed using classification systems, over time.Wound-healingrate was defined as average change in Sessing scale between two consecutive scoringsassessed twice per week (67), and as linear regression to PUSH values in the initial, second,fourth, sixth, and eighth week of the observation period (68,78). The majority of authorshave used a measure of the wound-healing rate that assumes linear wound extent variationover time. This assumption is misleading since dynamics is nonlinear regardless of how thewound extent is measured.

The goal of wound care is complete wound closure. Therefore, wound healing rateshould describe time needed to wound closure and it should be irrespective of woundaetiology, location, and treatment. Wound-healing rate expressed as absolute area healedper day tends to exaggerate the healing rates of larger wounds and healing rate expressed andas percentage of initial area healed per day tends to exaggerate the healing rates of smallerwounds. Wound-healing rate should not be affected by wound size, when wounds ofdiffering sizes are compared. Only wound-healing rate expressed as the advance of thewound margin toward the wound center per day is not influenced by initial wound size (73).The wound-healing rate defined as the advance of wound margin towards the wound centeris defined as

Q ¼ 2S0

p0

1

Tmm=day ð2Þ

where S0 is the initial wound area, p0 is the initial perimeter, and T is the time to completewound closure. Positive value of wound-healing rate indicates healing wounds and negativevalue of the wound-healing rate is the estimate of wound growth velocity towards its doubleinitial area. For the wound healing rate Q to be appropriately calculated, we have to followthe wound-healing process till the complete wound closure. Because clinical trials arefinancially and time limited, the time to complete wound closure has to be predicted fromcollected wound extent measurements in observation period, which may be much shorterthan time to the complete wound closure. However, prediction of the time to completewound closure could help clinicians to early detect not efficiently treated wounds. To predicttime to complete wound closure wound extent has to be periodically measured and a knownmodel fitted to the collected data. From calculated values of model parameters, the time tocomplete wound closure can be calculated. Since exponential function reaches its asymptoteat infinite time, wound can be defined to be closed when the mathematically predictedwound area is smaller than 5% of initial value and at the same time smaller than 100 mm2.

V. CLINICAL STUDIES

During more than a decade lasting clinical use of electrical stimulation, data concerningpatients, wounds, and their treatment were assessed and documented. The Ethical Com-mittee of the Republic of Slovenia approved the study. The patients were examined byphysician for an initial assessment of their wound status and relevant factors. The ex-perimental procedure was explained to them and all patients agreed to participate in the


study by signing an informed consent form. Together, 266 patients with 390 wounds wererecorded in our computer database up to date. Unfortunately, many patient and wounddata are missing, and not all wounds were followed regularly or until the complete woundclosure, which is relatively common problem in clinical trials. Wound case inclusion criteria(initial wound area larger than 1 cm2 and at least four weeks of wound healing processfollow-up) were fulfilled in 300 wound cases (214 patients). Our study enrolled wounds ofvarious aetiologies (e.g., vascular ulcerations, amputation wounds, pressure ulcers, neuro-pathic ulcerations), locations, and different treatments in patients with different primarydiagnoses (e.g., spinal cord injury, diabetes mellitus, sclerosis multiplex, vascular diseases).

All patients received conservative treatment of their chronic wounds. The conservativetreatment included initial selective debridement, the application of a new standard dressingto the chronic wound two or more times per day, as needed, and broad-spectrum antibioticsin cases of infection, which were rather rare. Fifty-four (18.0%) wounds received onlyconservative treatment. In addition to the conservative treatment, 23 (7.7%) woundsreceived sham treatment, where electrodes were applied to the intact skin on both sides ofthe wound for two hours daily and connected to stimulators, in which, however, the powersource was disconnected and they delivered no current. Two different modes of electricalstimulation were used: direct and biphasic current. Forty-two (14.0%) wounds werestimulated with direct current of 0.6mA for 0.5 h, 1 h, or 2 h daily. Positive stimulationelectrode overlaid the wound, surface and negative electrode was placed on the intact skinaround the wound, or both electrodes were placed on the healthy skin at the wound edgeacross the wound, one of them being positive and the other negative. We have pooleddifferent electrode placements in direct current stimulation group in spite of the difference ineffectiveness of direct current stimulation (34).We did this for two reasons: in literature bothelectrode placements were shown to accelerate chronic wound healing; and in this way wekept otherwise small direct current stimulation group of wounds at the size that allowed usstatistical analysis. One hundred eighty-one (60.3%) wounds were stimulated with biphasic,charge-balanced current pulses (79) for 0.5 h, 1 h, or 2 h daily with electrodes placed on bothsides of the wound. The pulse duration was 0.25 ms and at a repetition rate of 40 Hz. The 4-sstimulation trains were rhythmically alternated with pauses of the same duration. Thepulsed currents produce tetanic contraction of the stimulated tissue, which is kept at aminimum level (adjusted by the stimulation amplitude, usually at 15 to 25mA) to preventmechanical damage of the newly formed tissue (Fig. 2).

The currents were applied across the wound by a pair of self-adhesive skin electrodes(Encore TM Plus, Axelgaard Manufacturing Co. Ltd.) attached to the healthy skin at theedge of the wound. In direct stimulation group, where positive stimulation electrodeoverlaid the wound surface, the wound surface was covered with sterile gauze, soaked inphysiological solution, on top of which a conducting rubber electrode was applied. Thisassured uniform current distribution throughout the entire wound area. Four self-adhesiveelectrodes were attached to the intact skin around the wound, representing the ring-shapednegative electrode. At the beginning of our study in 1989, wounds were randomly assignedinto four treatment groups: conservative treatment, sham treatment, biphasic currentstimulation, and direct current stimulation. Since Jercinovic et al. (33) showed thatstimulated wounds were healing significantly faster than conservatively or sham treatedwounds, it was not ethical to keep including patients in those groups. After Karba et al. (34)reported that electrical stimulation with direct current is effective only if positive electrode isplaced on the wound surface, which is an invasive method, only stimulation with biphasiccurrent pulses was used. Therefore, the group of patients stimulated with biphasic currentpulses is larger than other groups of patients.


For the evaluation of the efficacy of particular treatment modality or for the evaluationof the influence of wound and patient attributes on wound healing, wound area wasperiodically followed. Wound shape was approximated with an ellipse and thus it wasenough to periodically followmutually perpendicular diameters of the wound. Fromwounddiameters, the wound area, perimeter, and width-to-length ratio were calculated. Asalternative measure of wound extent we used the four-stage Shea grading system (65).Wound depth and grade were collected only at the beginning of treatment. Wounds weretreated daily till complete wound closure. If wound did not completely heal within theobservation period, the patient continued his treatment at home, but follow-ups werediscontinued because the reliability of the home treatment was questionable. Among 300wound cases, in 174 cases wounds were followed untill complete wound closure, while in 126cases time to complete wound closure was estimated (72,73). No significant differencebetween actual time to complete wound closure and estimated one from wound extentmeasurements in observation period longer than 4 weeks was observed. Because time tocomplete wound closure was found dependent on initial wound extent, a measure of thewound healing rate an average advance of the wound margin towards the wound centre wasused. In Table 2 wound, patient, and treatment data collected in our computer database arelisted. These data were selected to be attributes of chronic wound description. All listedattributes except wound extent were collected at the beginning of wound treatment. Inaddition, wound extent was followed weekly during the observation period or until thecomplete wound closure.

Plotting percentage of healed wounds against the time elapsed from the beginning of thetreatment (Fig. 3) revealed differences between the four treatment groups. Electricallystimulated wounds healed at higher rate and extent than other wounds. Over 90% ofelectrically stimulated wounds healed within 60 weeks, while only 70% of sham treatedwounds and 72% of conservative treated wounds healed within the same period. Thewound-healing rate revealed significant differences between four treatment groups. Resultsof Kolmogorov-Smirnov Two Sample nonparametric test comparing treatment modalities( p values) revealed that wounds treated with biphasic current stimulation healed signifi-

Figure 2 Electrical properties of biphasic electrical current stimulation.


Table 2 Wound, Patient, andTreatment Data CategoriesCollected in a Database

During More Than a Decadeof Using Electrical Stimulationat the Institute of the Republic

of Slovenia for Rehabilitation

Wound dataLength of the woundWidth of the wound

DepthGrade (65)Date of wound appearance

Date of treatment beginningAetiologyLocation

Patient dataSexDate of birthNumber of wounds

DiagnosisDate of spinal cord injuryDegree of spasticity

Treatment dataType of treatmentDaily duration of treatment

Duration of treatment

Figure 3 Percentage of healed wounds against time elapsed from beginning treatment for fourtreatment modalities: (–.–) biphasic current stimulation; (–j–) direct current stimulation; (–n–)

conservative treatment; (�w�) sham treatment (from Ref. 83).


cantly faster than conservative or sham treated wounds. No significant difference was foundin healing rates between wounds treated with direct current and wounds treated withbiphasic current pulses. Difference in healing rates between direct current and conservativeor sham treatment was considerable, in favor of direct current, although it was notsignificant. Conservative or sham treated wounds healed at the same rate.

A. Prognostic Factors in the Prediction of Wound Healing

However, dynamics of the wound healing process does not depend only on the type of thetreatment, but depends also on wound and patient attributes. The aims of our study were todetermine the effects of wound, patient, and treatment attributes on wound-healing processand to propose a system for prediction of the wound healing rate. Only a limited number ofgroups have investigated wound and patient attributes which affect chronic wound healing(74–76,80,81) and none of them incorporates electrical stimulation as the chronic woundtreatment modality. The quantity of available data from our clinical study of electricalwound healing permitted us to employ statistical tools and artificial intelligence methods foranalysis of the healing process itself, as well as of the effects of different therapeuticmodalities. In the first step of our analysis we determined which wound and patientattributes play a predominant role in the wound-healing process. Then we discussed thepossibility to predict wound-healing rate at the beginning of treatment based on initialwound, patient and treatment attributes. Finally we discussed the possibility to enhance thewound healing rate prediction accuracy by predicting it after a few weeks of wound healingfollow-up.

1. Wound-Healing Rate Prediction from the Model Wound-Healing Dynamics

We determined that the wound area variation over time has a delayed exponential behavior.Delayed exponential equation is thus the structure of mathematical model of the woundhealing process and by fitting this model to a particular chronic wound case; parameters ofthe model are calculated. At least four measurements of wound area (performed in at leastthree weeks) are needed before parameters of mathematical model can be estimated. Fromparameters of mathematical model the time to complete wound closure was estimated.

According to Eq. (2) the estimated wound healing rate was calculated. We found thatthe estimated wound healing rate after at least 4 weeks of wound follow-up did not differsignificantly from the actual one ( p z 0.2). However, if a wound extent was followed lessthan 4 weeks the difference was found to be significant. In clinical trials 4 weeks is a shortperiod, but in clinical practice a shorter time for treatment outcome prediction may berequired.

2. Statistical Analysis

Distribution of the wound healing rate was not normal; non-parametric statistical analysiswas therefore employed. To determine differences in distribution of quantitative attributesin groups formed by qualitative attributes we used the Kruskal-Wallis one-way analysis ofvariance. To test relationship of qualitative attributes, we used a chi-square test. Todetermine if two quantitative attributes are correlated, we used the Spearman correlationtest (rs = Spearman correlation coefficient, p = probability of being wrong in concludingthat there is a true association between the variables, and n = number of cases).

Statistical analysis revealed that the time to complete wound closure is correlated towound extent attributes, area (rs = 0.428, p < 0.001), and grade (rs = 0.388, p < 0.001).The wound-healing rate is not correlated to initial area, perimeter, or width to length ratiobut is moderately correlated to wound grade (rs=�0.237, p<0.001, n=281). Wounds of


higher grade were healing slower. Wound grade also tends to increase with increasing initialwound area (rs = 0.292, p < 0.001, n = 281).

Time elapsed from wound appearance to the beginning of treatment was modestlycorrelated to wound grade (rs=0.181, p=0.005, n=243), which can indicate that woundsshould be treated as soon as they appear. Therefore it was also expected that the wound notappropriately treated for a long period would heal slowly (negative correlation coefficientwhen comparing AppearStart with the wound healing rate) (rs = �0.215, p < 0.001,n = 243). A small initial wound area (rs = �0.261, p < 0.001, n = 178) of wounds thatappeared a long time after spinal cord injury (injuryappear), is probably a result of betterpatients self care.

Wounds on trochanter healed significantly slower ( p < 0.030) than wounds on otherlocations. Locations did not differ with respect to grade ( p = 0.236) but they differed withrespect to area ( p < 0.001), revealing significantly greater wounds on locations trochanterand sacrum than on gluteus or other locations. Wounds on trochanter, gluteus and sacrumwere all pressure ulcers. Patients with wounds on sacrum or trochanter were significantlyyounger ( p < 0.010) than patients with wounds on other locations.

Wounds of geriatric (healing rate= 0.271mm/day) and traumatic patients were healingsignificantly faster ( p = 0.005) than wounds of patients with other diagnosis: spinal cordinjury (0.173 mm/day), vascular insufficiency (0.171 mm/day), diabetes mellitus (0.102 mm/day) and multiple sclerosis (0.138 mm/day). We found diagnosis strongly related to woundaetiology ( p < 0.001).

Electrically stimulated wounds healed at higher rate and extent than other wounds.Over 90%of electrically stimulated wounds healed within 60weeks, while only 70%of shamtreated wounds and 72% of conservative treated wounds healed within the same period. Itwas found that wounds treated with biphasic current stimulation healed significantly fasterthan conservative ( p = 0.031) or sham ( p = 0.008) treated wounds. No significantdifference ( p = 0.365) was found in healing rates between wounds treated with directcurrent and wounds treated with biphasic current pulses. Difference in healing rates betweendirect current and conservative ( p = 0.085) or sham treatment ( p = 0.056) was consid-erable, in favor of direct current, although it was not significant. Conservative or shamtreated wounds healed at the same rate ( p = 0.607).

Wounds stimulated by biphasic current for 2 h daily healed at the same healing rate asthose stimulated for 0.5 h daily, while wounds stimulated for 1h daily healed significantly( p = 0.017) faster than wounds stimulated for 2 h or 0.5 h daily. A lack of wound casesstimulated for 1 h daily (n = 13) renders this result statistically unreliable. Further studyshould be performed to optimise daily duration of electrical stimulation.

3. Machine Learning Approach to Wound-Healing Rate Prediction

From results of statistical analysis reported above, it is obvious that the wound healing rateis directly dependent on wound treatment and wound grade, while interactions of otherwound and patient attributes on the wound healing rate are not easy to determine.Prognostic factors of wound healing are rarely analyzed in the literature and our studywas first attempt to incorporate electrical stimulation as the chronic wound treatmentmodality. We employed tree learning algorithms to build regression and classification treesto predict the wound healing rate based on initial wound, patient and treatment data. Wetested several algorithms for attribute selection among which RReliefF (82) for regressiontree generation was found to be the most effective (83). For models in leaves of the tree, themost appropriate were linear equations. A stopping rule of minimal five wound cases in aleaf was used. Since the sample size (n=300) wasmoderate, the 10-fold cross-validationwas


used as the error estimation method. The accuracy of regression trees was measured asrelative squared error (relative error) (84), which is always nonnegative and usually lessthan 1. Trees with relative error close to 0 produce good prediction of the wound healingrate, and trees with the relative error around 1 or even greater than 1 produce poorprediction.

Attributes partitioning powers calculated using machine learning algorithm RReliefFrevealed that initial wound area, followed by patient’s age and time fromwound appearanceto treatment beginning are the most prognostic attributes, followed by wound shape (width-to-length ratio), location of wound, and type of treatment. Generated regression trees withlinear equations in leaves for the wound healing rate prediction at the beginning of treatmenthad relative squared error greater than one, which means that resulting regression trees arenot usable. Adding the model estimate of the wound-healing rate in a set of variables usedfor regression tree generation reduced relative error of generated regression tree. Wound-healing rate estimated only after 1 week of wound area follow-up reduced the relative errorof generated regression tree to 0.64, similarly after 2 weeks to 0.35, after 3 weeks to 0.18(Fig. 4) and after 4 weeks of follow-up to 0.09. Afterwards relative error was slowlydecreasing to 0.06 in 6 weeks of follow-up. After 5 weeks, the wound-healing rate predictedby regression tree was equal to the healing rate estimated by the delayed exponential model.The predicted wound-healing rate in shorter period in addition depends on wound, patient,and treatment attributes. Rough estimation of wound healing rate can be determined onlyafter 2 weeks of wound healing follow-up. Type of treatment is indirectly included inregression trees as daily duration of treatment, which was zero in case of conservative orsham treated wounds. Important prognostic attributes are wound area, grade, shape (widthto length ratio), patients age, elapsed time from spinal cord injury to wound appearance, andelapsed time from wound appearance to the beginning of treatment.

Considering also prognostic factors: deep vein involvement, ankle/brachial pressureindex, liposclerosis, edema, exudates and granulation, which are reported in the literature(74,80) as prognostic factors, our prediction might be even more accurate. Regression treesin combination with prediction capability of delayed exponential model of wound healingdynamics are basis for the prognostic system for prediction of chronic wound healing rate.

B. Quantitative and Qualitative Changes in the Tissue After ElectricalWound Healing

The proof weather a method of treating wounds is successful is a matter of histologicalanalyses of the affected soft tissue before and after treatment (85,86). Reports of histological

Figure 4 Regression tree with linear equations in leaves for prediction of wound healing rate after3 weeks of treatment (from Ref. 83).


analyses of electrical wound healing are rare especially in clinical trials. At the Institute ofRehabilitation a histological study of electrical wound healing was done recently. The studyenrolled 50 patients with spinal cord injury, suffering from decubital ulcers of III degreeaccording to Shae scale (65) in the sacral area. A half of wounds were treated according todescribed biphasic electrical stimulation treatment and another half received only con-servative treatment. In five patients from each group a qualitative and a quantitativehistological analyses of the tissue samples (about 4 mm3) taken from the wound, on the linebetween the wound edge and freshly formed scar, were performed before the beginning oftreatment and after around 2 months, when the formed scar formed during the electricalstimulation was of considerable size.

Wound healing was followed as described in above clinical study section. Significantlyfaster healing of wounds in electrically stimulated group was observed. The histologicalpreparations were analyzed by a quantitative stereological method. Content of surfacecollagen in the preparations stained according to Masson and the surface density of bloodvessels was determined in the immunohistochemically stained preparations. The surfacepercentage of collagen was determined by using test system M-42 and the number of bloodvessels per surface unit by a semiautomatic IBAS 1000 image processing and analysissystem. Wounds treated by electrical stimulation had lower inflammatory response, highercollagen density as well as more intense process of angiogenesis. In electrically healed groupcollagen density increased in average 23%,while in the control group decreased by 2%of theinitial surface in two months time period. The area density of blood vessels was higher inelectrically stimulated wounds, and in poststimulation period the blood vessels were foundto be reaching essentially higher towards the wound surface than in the nonstimulatedwounds, in fact, almost as far as the crust.

In stimulated wounds endothelial cells were flat, the blood vessels lumina broad witherythrocytes clearly visible within them. In control group endothelial cells were thickened,cubically shaped, with round nuclei, and no erythrocytes were visible within blood vesselslumina. Also previous in vitro studies (37,87) reported flatter endothelial cells exposed toelectromagnetic or electric field, which are of cubic shape when not exposed to the field.

The study showed that the intercellular substance is dominated by fibrin whereas morecollagen was found in the sample preparations of electrically healed wounds. The conclusionis that electrical stimulationmay exert the release ofmediators responsible for the increase incollagen synthesis in fibroblasts or the shrinking of myofibroblasts. Furthermore the studyshowed that electrical healing has a favorable effect on blood circulation in the wound,improves blood circulation in the tissue surrounding the wound and improves the quality ofposttreatment scar.

VI. CONCLUSIONS

One of the largest clinical studies of electrical wound healing and its outcomes are presented.Electrically stimulated wounds healed faster and at greater percentage than conservative orsham treated wounds. We noticed slightly slower healing of wounds treated with directcurrent than wounds treated with biphasic current, but both treatment modalities acceleratewound healing of chronic wounds. Histological analysis confirmed positive effects ofbiphasic current electrical stimulation, such as improved blood circulation in the woundand surrounding tissue, as well as improved posttreatment scar.

Electrical treatment regime should in future be optimized regarding electrical param-eters used and daily duration of treatment. However it should also be determined whichtreatment regimes apply best for different wound aetiologies. Unified wound-healing


quantification and documentation will enable researchers to optimize electrical woundhealing and promote it in clinical practice.

It was demonstrated that wound healing process can be weekly followed by simplewound area and perimeter measurements. In future non contact measuring devices willsimplify wound extent measurement and documentation. For accurate wound-healing rateestimation, wounds should be followed at least 4 weeks, while using generated regressiontrees follow-up can be reduced to 3 weeks for wound healing estimation with relative error0.18. Therefore, the wound-healing rate or the time to complete wound closure can beestimated after 3 weeks of treatment, which can help to formulate appropriate managementdecisions, reduce the cost, and orient resources to those individuals with poor prognosis.

ACKNOWLEDGEMENTS

The authors are in depth to Prof. DamijanMiklavcic for his valuable help during the chapterpreparation. This work was supported by Slovenian Ministry for Education, Science andSport.

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